Parallel solid-phase synthesis of disubstituted 3-(1H-benzo[d]imidazol-2- yl)imidazolidine-2,4-diones and 3-(1H-benzo[d]imidazol-2-yl)-2- thioxoimidazolidin-4-ones

Article abstract of DOI:10.1016/j.tetlet.2011.10.064

A multistep approach to construct novel 3-(1H-benzo[d]imidazol-2-yl) imidazolidine-2,4-diones and 3-(1H-benzo[d]imidazol-2-yl)-2-thioxoimidazolidin- 4-ones from commercially available amino acids, amines, and carboxylic acids is described. Coupling of Fmo

Full text of DOI:10.1016/j.tetlet.2011.10.064

Tetrahedron Letters 52 (2011) 7030–7033
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Parallel solid-phase synthesis of disubstituted 3-(1H-benzo[d]imidazol-2-yl)
imidazolidine-2,4-diones and 3-(1H-benzo[d]imidazol-2-yl)-
2-thioxoimidazolidin-4-ones
Sureshbabu Dadiboyena a, Adel Nefzi a,b,
⇑
a Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA
b Florida Atlantic University, Boca Raton, FL 33431, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A multistep approach to construct novel 3-(1H-benzo[d]imidazol-2-yl)imidazolidine-2,4-diones and
3-(1H-benzo[d]imidazol-2-yl)-2-thioxoimidazolidin-4-ones from commercially available amino acids,
amines, and carboxylic acids is described. Coupling of Fmoc-amino acid to resin-bound aminobenzimid-
azole provided following Fmoc elimination free amine. Treatment of the free amine with 1,10-carbonyl-
diimidazole or 1,10-thiocarbonyldiimidazole furnished the corresponding hydantoins and thiohydantoins
via intramolecular cyclization. The desired aminobenzimidazole tethered hydantoins or thiohydantoins
were isolated in good yields.
Received 21 September 2011
Revised 6 October 2011
Accepted 11 October 2011
Available online 17 October 2011
Keywords:
Solid phase synthesis
Benzimidazole
Amino acid
Ó 2011 Elsevier Ltd. All rights reserved.
Hydantoin
Thiohydantoin
Heterocycles
Intramolecular cyclization
Solid phase organic synthesis (SPOS) is a powerful technique for
the rapid synthesis of small molecules endowed with potential bioac-
tive properties.1–4 A recurring featureof this approachis thesynthesis
of substituted heterocycles of structural diversity which aroused
greater attention and have proven to be broadly and economically
useful as therapeutic agents.4,5 Benzimidazolesarean important class
of heterocycles displaying a wide variety of biological properties,6–10
they represent a key structural motif in angiotensin-II-antagonists,
anticoagulants, and gastric proton-pump inhibitors.8–16 We previ-
ously reported the application of resin-bound amino-benzimidazoles
as a template for the synthesis of a variety of heterocyclic compounds
such as tetracyclic benzimidazoles,13 triazino-benzimidazoles,14 and
branched thiohydantoin benzimidazoline-thiones.16 In continuation
of our efforts directed toward the synthesis of combinatorial libraries
of heterocyclic compounds utilizing amino acids and benzimidazole
scaffolds,11–16 we describe herein a multistep approach for the paral-
lel solid-phase synthesis of compounds containing amino-benzimid-
azole tethered to pharmacologically known hydantoin or
thiohydantoin.
dence of this pharmacophore in several drugs and drug-like
candidates has resulted in the development of a plethora of methods
to construct this valuable fragment.18,22–30 In addition to hydantoins,
thiohydantoins constitute analogous structural frameworks of syn-
thetic and biomedical importance.17,18,31–35 Due to aforementioned
applications, the synthesis of hydantoins and thiohydantoins units
has received greater attention and few reports representing pharma-
ceutical and medicinal applications of hydantoins and thiohydanto-
ins (Fig. 136–42).
We envisioned the preparation of hydantoins and thiohydan-
toin nuclei from the amino acid coupled benzimidazole precursor
11 following intramolecular cyclization. Aminobenzimidazoles 9
required for the synthesis are conveniently accessed in several
steps from the corresponding resin bound 4-fluoro-3-nitrobenzoic
acid.11–16 The retrosynthetic rationale for the synthesis of amino-
benzimidazole tethered hydantoins and thiohydantioins is illus-
trated in Scheme 1.
The synthesis of all compounds described was carried out utiliz-
ing the tea-bag technology, wherein the resin is packed within
sealed polypropylene mesh packets.15 This method is convenient
and allow the parallel synthesis of a large number of compounds
in a specified time period. Based on previous literature prece-
dents,13–15 we introduced the first position (R1) of diversity with
five different amines via nucleophilic substitution of 4-fluoro-3-
nitrobenzoic acid, and the second position (R2) of diversity was
Hydantoins represent ubiquitous structural core sporadically
found in a number of natural products 1–6,17,18 and bioactive hetero-
cycles such as phenytoin 7 and mephenytoin 8.19–21 The high inci-
⇑
Corresponding author. Tel.: +1 (772) 345 4739; fax: +1 (772) 345 3649.
E-mail addresses: anefzi@tpims.org, adeln@tpims.org (A. Nefzi).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.064

S. Dadiboyena, A. Nefzi / Tetrahedron Letters 52 (2011) 7030–7033
7031
H
R2
Y
N
R1O
O
R1
N
H
N
X
H
N
O
N
O
NH
H
N
NH
HN
N
O
HN
R2
O
NH2
O
O
Parazoanthine A (1): R1 = R2 = H
Parazoanthine B (2): R1 = R2 = H
Aplysinopsins (6)
R1, R2 = H, Me; X = O, NH
Y = H, Br
5,6
7
Phenytoin ( )
8
Mephenytoin ( )
5,6
3
Parazoanthine C ( ): R1 = Me, R2 = H
4
Parazoanthine D ( ): R1 = Me, R2 = Br
5,6
5
Parazoanthine E ( ): R1 = Me, R2 = Br
Gastric Proton Pump Inhibitors6,7
Prevalent core for marine natural products17,18
NMDA antagonists6,7
Found in many pharmaceutically
relevant molecules21
Angiotensin-II-antagonists7
O
O
Anticonvulsant and antimuscarinic activities37,38
R2
NH
N
H2N
Anti-helminthic, Antiviral,
N
Antiallergic, Antineoplastic activities6,7
N
Antiulcer, Antiviral and antiarrythmic activities38,40
R1
X
Potent inhibitor of muscle and liver
glycogen phosphorylases42
Inhibition and Dispersion of Gram-
positive bacterial biofilms8
Pro-drug form of D-penicillamine39
Anti-bacterial agents9
Insulinotropic effects in INS-1 cells41
Modulators of small conductance-Calcium
activated Potassium channels
Submicromolar affinity in binding assays at
recombinant human somatostatin receptors36
10
Figure 1. Natural and pharmaceutically occurring hydantoins and some reported bioactive properties of hydantoin/thiohydantoin structural motifs.
O
O
O
N
N
N
H
O
R2
NH
NH2
+
O
NH2
N
N
H2N
N
N
N
Intramolecular Cyclization
H2N
R1
NH R2
R2
9
R1
X
Fmoc
OH
R1
N
H
12
X =O,
O
X =S, 13
10
11
Scheme 1. Retrosynthetic illustration of synthetic work to construct hydantoins and thiohydantoins.
O
O
O
O
NH2
R2
NO2
N
N
N
N
N
H
N
H
N
H
a,b
Fmoc
OH
+
NH2
NH R2
N
H
3 steps
F
O
R1
R1
14
9
11
O
O
O
O
R2
R2
NH
N
N
N
N
H
d
H2N
X = O, 12
13
N
N
X = S,
NH
N
R1
X
R1
X
15
c
11
H
N
X
R2
O
N
N
O
N
H
16
X = O,
N
R1
X = S, 17
Scheme 2. Parallel solid-phase synthesis of hydantoin and thiohydantoin derivatives. Reagents and condtions: (a) PyBOP (8 equiv, 0.5 M anhyd. DMF), HOBt (8 equiv), DIEA
(8 equiv), 12 h, rt; (b) 20% piperidine/DMF, 20 min (2ꢀ), rt; (c) 1,10-carbonyldiimidazole (or) 1,10-thiocarbonyldiimidazole, anhyd. DMF, 80 °C, 12 h; (d) HF/anisole (99:1), 0 °C,
90 min.

7032
S. Dadiboyena, A. Nefzi / Tetrahedron Letters 52 (2011) 7030–7033
Table 1
Hydantoins and thiohydantoins isolated from intramolecular cyclization
O
O
O
O
R2
NH
N
N
N
N
H2N
H2N
12p-t
13a-e
X = O;
X = S;
N
N
N
12a-o
R1
O
R1
X
Entry
R1
R2 (amino acid)
Mass calcd/found (MH+)
Yieldsa (%)
12a
12b
12c
12d
12e
12f
12g
12h
12i
Cyclopentyl
n-Butyl
Cyclohexanemethyl
i-Butyl
3-(trifluoromethyl)benzyl
Cyclopentyl
n-Butyl
Cyclohexanemethyl
i-Butyl
3-(Trifluoromethyl)benzyl
Cyclopentyl
n-Butyl
Cyclohexanemethyl
i-Butyl
3-(Trifluoromethyl)benzyl
Cyclopentyl
n-Butyl
Cyclohexanemethyl
i-Butyl
3-(Trifluoromethyl)benzyl
Cyclopentyl
n-Butyl
Cyclohexanemethyl
i-Butyl
Phe
Phe
Phe
Phe
Phe
Leu
Leu
Leu
Leu
Leu
Tyr
Tyr
Tyr
Tyr
Tyr
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
417.4/418.2
405.4/406.3
445.5/446.3
405.4/406.2
507.5/508.3
383.4/384.2
371.4/372.3
411.5/412.2
371.4/372.2
473.4/474.1
433.4/434.3
421.4/422.2
461.5/462.3
421.4/422.2
523.5/524.3
367.4/368.4
355.4/356.4
395.4/386.2
355.4/356.4
457.4/458.2
383.5/384.3
371.5/372.3
411.5/413.4
371.5/372.2
473.5/474.4
71
92
93
89
85
81
83
96
74
98
81
72
91
95
77
92
95
81
91
73
91
88
92
89
65
12j
12k
12l
12m
12n
12o
12p
12q
12r
12s
12t
13a
13b
13c
13d
13e
3-(Trifluoromethyl)benzyl
The products were run on a Vydac column, gradients 5–95% formic acid in ACN in 7 min.
a
The yields are based on the weight of purified products and are relative to the initial loading of the resin. (The purity of the purified compounds is higher than 95% for all
the compounds.)
δ = 165-180 ppm
ꢁ165–180 ppm, which is in accordance with our experimental
H
O
N
data (Fig. 2).43 All of these intramolecular cyclizations leading to
the formation of hydantoins or thiohydantoins occurred in good
isolated yields and the results are shown in Table 1.
O
O
O
C
N
N
H
2N
O
H2N
A
B
N
A
B
N
C
NH
N
N
δ = 190-210 ppm
In summary, we have developed an efficient solid-phase syn-
thesis of aminobenzimidazole tethered hydantoins and thiohydan-
toins via intramolecular cyclization as an essential step. The
coupling of resin-bound aminobenzimidazoles13–16 with several
amino acids led to the formation of benzimidazole coupled amino
acid residues. Following Fmoc elimination, the free amino group
was used as the precursor to prepare a library of hydantoins and
thiohydantoins tethered benzimidazole.43
O
16
12d
Figure 2. 13C NMR based structural assignment of hydantoin nuclei.
introduced by coupling resin-bound aminobenzimidazole 9 with
four different amino acids using PyBOP in anhydrous DMF condi-
tions. The protected Fmoc group was later deprotected using 20%
piperidine to afford the free amine 11. Treatment of the amine
11 with 1,10-carbonyldiimidazole or 1,10-thiocarbonyldiimidazole
generated an intermediate isocyanate or isothiocyanate which,
later underwent intramolecular cyclization pathway and furnished
the corresponding hydantoins or thiohydantoins, respectively.43
The synthetic protocol for the parallel solid-phase synthesis of
hydantoins is outlined in Scheme 2.
Acknowledgments
The authors would like to thank the State of Florida Funding,
NIH (1R03DA025850-01A1, Nefzi; 5P41GM081261-03, Houghten;
3P41GM079590-03S1, Houghten) for providing generous financial
support.
The competitive reaction leading to the formation of the fused
tricyclic diketo-triazepines 16 and 17 was not observed. The struc-
tural assignment of hydantoin was identified based upon the un-
ique nature of the 13C chemical shift of the –(CO)NH joining the
amino acid and benzimidazole. The carbonyl in diketotriazepine
16 or 17, is in conjugation with the imine C@N bond, and would
tend to exhibit 13C chemical shift greater than 200 ppm. However,
in case of hydantoin, the two carbonyls are attached to same nitro-
gen, and the 13C chemical shift for those compounds would be
References and notes
1. Ziegert, R. E.; Torang, J.; Knepper, K.; Brase, S. J. Comb. Chem. 2005, 7, 147.
2. Kundu, B. Curr. Opin. Drug Discovery Dev. 2003, 6, 815.
3. Feliu, L.; Vera-Luque, P.; Albericio, F.; Alvarez, M. J. Comb. Chem. 2009, 11, 175.
4. Franzen, R. G. J. Comb. Chem. 2000, 2, 195.
5. Krchnak, V.; Holladay, M. W. Chem. Rev. 2002, 102.
6. McCanley, J. A.; Munson, P. M.; Thompson, W.; Claremon, D. A. WO0132634,
2000.
7. Nohara, A.; Maki, Y. US4628098, 1986.
8. Rogers, S. A.; Huigens, R. W., III; Melander, C. J. Am. Chem. Soc. 2009, 131, 9868.

S. Dadiboyena, A. Nefzi / Tetrahedron Letters 52 (2011) 7030–7033
7033
9. Seth, P. A.; Jefferson, E. A.; Risen, L. M.; Osgood, S. A. Bioorg. Med. Chem. Lett.
2003, 13, 1669.
36. Scicinski, J. J.; Barker, M. D.; Murray, P. J.; Jarvie, E. M. Bioorg. Med. Chem. Lett.
1998, 24, 3609.
10. Sorenson, U. S.; Teuber, L.; Peters, D.; Strobaek, D.; Johansen, T. M.; Nielsen, K.
S.; Christophersen, P. U.S. Patent 514395; 20080200529.
11. Acharya, A. N.; Thai, C.; Ostresh, J. M.; Houghten, R. A. J. Comb. Chem. 2002, 4,
496.
12. Acharya, A. N.; Ostresh, J. M.; Houghten, R. A. Tetrahedron 2002, 58, 2095.
13. Hoesl, C. E.; Nefzi, A.; Houghten, R. A. J. Comb. Chem. 2004, 6, 220.
14. Hoesl, C. E.; Nefzi, A.; Houghten, R. A. Tetrahedron Lett. 2003, 44, 3705.
15. Houghten, R. A. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 5131.
16. Nefzi, A.; Giulianotti, M.; Houghten, R. A. Tetrahedron Lett. 2000, 41, 2283.
17. Cachet, N.; Genta-Jouve, G.; Regalado, E. L.; Mokrini, R.; Amade, P.; Culioli, G.;
Thomas, O. P. J. Nat. Prod. 2009, 72, 1612.
37. (a) Hudkins, R. L.; DeHaven-Hudkins, D. L.; Doukas, P. Bioorg. Med. Chem. Lett.
1997, 8, 9979; (b) Rump, S.; Ilczuk, I.; Rabsztyn, T.; Walczyna, K. Pharmazie
1981, 36, 780.
38. El-Barbarbary, A. A.; Khodair, A. I.; Pedersen, E. B. Arch. Pharm. (Weinheim, Ger.)
1994, 327, 653.
39. Poupaert, J. H.; Mukarugambwa, S.; Dumont, P. Eur. J. Med. Chem. Chim. Ther.
1980, 15, 511.
40. Lopez, C. A.; Trigo, G. G. Adv. Heterocycl. Chem. 1985, 38, 177.
41. Bozdag, O.; Verspohl, E. J.; Ertan, R. Arzneimittelforschung 2000, 50, 626.
42. Osz, E.; Somsak, L.; Szilagyi, L.; Kovacs, L.; Docsa, T.; Toth, B.; Gergely, P. Bioorg.
Med. Chem. Lett. 1999, 9, 1385.
18. Jakse, R.; Kroselj, V.; Recnik, S.; Sorsak, G.; Svete, J.; Stanovnik, B.; Grdadolnik, S.
G. Z. Naturforsch 2002, 57b, 453.
19. Rodgers, T. R.; LaMontagne, M. P.; Markovac, A.; Ash, A. B. J. Med. Chem. 1977,
20, 591.
43. General procedure for the solid-phase synthesis of amino-benzimidazole tethered
hydantoins and thiohydantoins: p-Methylbenzhydrylamine (MBHA) resin
(100 mg, 1.10 mequiv/g, 100–200 mesh) was sealed inside a polypropylene
mesh packet. Polypropylene bottles were used for all of the reactions. Resin
20. Docsa, T.; Czifrak, K.; Huse, C.; Somsak, L.; Gergely, P. Mol. Med. Rep. 2011, 4,
477.
21. Bac, P.; Maurois, P.; Dupont, C.; Pages, N.; Stables, J. P.; Gressens, P.; Evrard, P. J.
Neurosci. 1998, 18, 4363.
22. Muccioli, G. G.; Poupaert, J. H.; Wouters, J.; Norberg, B.; Poppitz, W.; Scriba, G.
K. E.; Lambert, D. M. Tetrahedron 2003, 59, 1301.
23. Nefzi, A.; Giulianotti, M.; Truong, L.; Rattan, S.; Ostresh, J. M.; Houghten, R. A. J.
Comb. Chem. 2002, 4, 175.
24. Gao, M.; Yang, Y.; Wu, Y.-D.; Deng, C.; Shu, W.-M.; Zhang, D.-X.; Cao, L.-P.; She,
N.-F.; Wu, A.-X. Org. Lett. 2010, 12, 4026.
25. Nefzi, A.; Ostresh, J. M.; Giulianotti, M.; Houghten, R. A. Tetrahedron Lett. 1998,
39, 8199.
bound amino-benzimidazoles were synthesized according to a previous
literature.13–16 Fmoc-amino acid (8 equiv, 0.2 M in anhyd DMF) was coupled
to MBHA resin bound benzimidazole for 12 h at room temperature using the
coupling reagent PyBOP (8 equiv, 0.2 M), DIEA (8 equiv, 0.2 M) followed by
washes with DMF (3ꢀ) and DCM (3ꢀ). Following Fmoc deprotection with a
solution of 20% piperidine in DMF, the resin-bound N-terminal amino acid
residue
was
treated
with
1,10-carbonyldiimidazole
(1,10-
thiocarbonyldiimidazole) in anhydrous DMF (0.2 M) at 80 °C for 12 h. The
reaction mixture was decanted, and the resulting resin-bound hydantion
(thiohydantoin) product was washed with DMF (3ꢀ) and DCM (3ꢀ). The resin
was cleaved with HF/anisole for 90 min at 0 °C, and the desired hydantoin
(thiohydantoin) was obtained following extraction with 95% AcOH in H2O and
26. Boeijen, A.; Kruijtzer, J. A. W.; Liskamp, R. M. J. Bioorg. Med. Chem. Lett. 1998, 8,
2375.
27. Mahmoodi, N. O.; Khodaee, Z. ARKIVOC 2007, 29.
28. Gong, Y.-D.; Sohn, H.-Y.; Kurth, M. J. J. Org. Chem. 1998, 63, 4854.
29. Baccolini, G.; Boga, C.; Delpivo, C.; Micheletti, G. Tetrahedron Lett. 2011, 52,
1713.
30. Said, A. M.; Savage, G. P. J. Org. Chem. 2011, 76, 6946.
31. Lin, M.-J.; Sun, C.-M. Tetrahedron Lett. 2003, 44, 8739.
32. Kumar, P.; Chauhan, P. M. S. Tetrahedron Lett. 2008, 49, 5475.
33. Gasch, C.; Merino-Montiel, P.; Lopez, O.; Fernandez-Bolanos, J. G.; Fuentes, J.
Tetrahedron 2010, 66, 9964.
34. Cherouvrier, J.-R.; Carreaux, F.; Bazureau, J. P. Tetrahedron Lett. 2002, 43, 8745.
35. Jesper, R. S.; Lau, J. F.; Bondensgaard, K.; Hansen, B. S.; Begtrup, M.; Ankersen,
M. Bioorg. Med. Chem. Lett. 2004, 14, 317.
lyophilization as a white powder. The final products were purified by
preparative reverse-phase HPLC. NMR data for entry 12b: 1H NMR (DMSO-
d6): d 0.75 (m, 3H), 0.92 (t, J = 7.5 Hz, 2H), 1.23 (s, 1H), 1.30–1.35 (m, 2H), 3.12
(br s, 2H), 3.67–3.75 (m, 1H), 4.89 (br s, 1H), 7.27–7.38 (m, 6H), 7.63–7.65 (m,
1H), 7.87 (d, J = 10 Hz, 1H), 7.98–8.01 (m, 1H), 8.22 (s, 1H), 8.98 (br s, 1H); 13C
NMR: d 13.5, 19.0, 43.0, 58.0, 110.7, 119.2, 123.0, 127.1, 128.3, 128.8, 130.0,
139.6, 140.0, 153.5, 168.0; LC–MS m/z data calcd for C22H23N5O3 (MH+): 405.4;
found: 406.3; NMR data for entry 12d: 1H NMR (DMSO-d6): d 0.50–78 (m, 4H),
0.91 (d, J = 7 Hz, 2H), 1.23 (s, 1H), 3.12–3.13 (m, 2H), 3.67 (m, 1H), 3.91 (d,
J = 7.5 Hz, 1H), 4.90 (br s, 1H), 7.18 (d, J = 5 Hz, 1H), 7.28–7.38 (m, 6H), 7.67–
7.72 (m, 1H), 7.87 (d, J = 9.8 Hz, 1H), 7.98–8.02 (m, 1H), 8.22 (br s, 1H), 8.97 (br
s, 1H); 13C NMR: d 19.5, 27.1, 50.2, 58.1, 111.0, 119.1, 123.0, 128.1, 128.4, 128.8,
128.9, 130.0, 139.92, 139.98, 153.5, 168.0; LC–MS m/z data calcd for
C
22H23N5O3 (MH+): 405.4; found: 406.3.